Neurofilamentous changes are the pathological hallmarks of a variety of chronic diseases of both the central and the peripheral nervous systems. The normal regulation of axonal neurofilament content and its alterations in disease are fundamental problems in cellular neurobiology and neuropathology. Alterations in neurofilament content could in theory result from alterations in axonal transport or perikaryal synthesis of neurofilaments. In the first five years of this project we focused on a model of selective alteration in neurofilament transport, intoxication with beta, beta'-iminodipropionitrile (IDPN). Recently we have complemented these studies with an examination of a model of reordered perikaryal synthesis of cytoskeletal proteins, without alterations in their transport kinetics. This model, axotomy, produces selective reductions in perikaryal levels of mRNA's for the neurofilament 68KD protein, and elevations in levels of mRNA's for tubulin and actin. The morphologic consequence of reordered perikaryal synthesis is somatofugal axonal atrophy. In recent studies of a series of model neuropathies we have found elements of both changes in neurofilament kinetics and somatofugal axonal atrophy. In the proposed studies we will examine the changes in perikaryal synthesis in selected models of neuronal disease, asking if there are disease-specific differences among these models, or if there is a single stereotyped response to a variety of axonal and neuronal injuries. In related experiments we will ask what variables initiate reordered perikaryal synthesis of cytoskeletal elements and consequent somatofugal atrophy. These studies should point toward potential "signals" or trophic influences regulating perikaryal function. Elucidation of these influences will have fundamental implications for normal neuronal maintenance and chronic neuronal degenerations. The second set of proposals will utilize axonal transport techniques and quantitation of the cytoskeletal elements to reconstruct the normal economy of the cytoskeleton. We will examine the extent of a possible stationary cytoskeletal phase and the state of assembly of tubulin in different regions of long axons. This system should then allow new insights into the sequence of changes in neuronal disorders.